This Program Project Grant (PPG) application stresses innovative clinical cancer immunotherapy trials based on our current understanding of innate immunology, as well as basic investigation into innate immune effector cell function in preparation for subsequent, more refined clinical cancer immunotherapy trials. Project 1 is focused on monoclonal antibody therapy for the treatment of non-Hodgkin.s lymphoma (NHL). In preclinical studies performed in the SCID-human chimeric mouse model of malignant human lymphoproliferation, the combined administration of rituximab plus interleukin (IL)-2 is curative, while the administration of either agent alone is ineffective. Mechanistic studies in the model are underway. The first clinical study will be a combination of rituximab + IL-2 for the treatment of relapsed NHL. A second clinical trial will examine pro-inflammatory cytokine blockade as a means to enhance efficacy and decrease toxicity associated with agents like rituximab and Campath. Additionally it will focus on clinical trials that are derived from basic studies in natural killer (NK) cell biology. Specifically, we will be investigating the co-administration of IL-2 and Flt3 ligand for their synergy in expanding NK cells in-patients with HIV and HIV associated malignancy. Projects 2-4 each investigate one aspect of either monocyte/macrophage or NK cell biology with the notion that improved understanding of innate immune effector cell function will contribute to the design and implementation of the subsequent set of immunotherapy trials. Project 2 is focused on Fc?R signaling in monocytes with broad application to NK cell biology; Project 3 investigates the regulation of activation and tumor cell recognition within two newly identified subsets of human NK cells; Project 4 uses murine models to assess the role of co-stimulatory molecules in NK cell recognition of tumor targets and characterize NK subsets similar to those found in humans. The PPG is supported by 4 cores: Administration, Biostatistics, Correlative Science and Mouse Facilities. The overall goal is to rapidly introduce innovative clinical trials testing laboratory-based hypotheses, while pursuing additional basic investigation of innate immunity for subsequent cancer immunotherapy trials.